tbuckley/cabot-search huggingface dataset:
Protein tyrosine kinase 2b inhibition reverts niche-associated resistance to tyrosine kinase inhibitors in AML
Authors: Catana Allert, Alexander Waclawiczek, Sarah Miriam Naomi Zimmermann, Stefanie Göllner, Daniel Heid, Maike Janssen, Simon Renders, Christian Rohde, Marcus Bauer, Margarita Bruckmann, Rafael Zinz, Cornelius Pauli, Birgit Besenbeck, Claudia Wickenhauser, Andreas Trumpp, Jeroen Krijgsveld, Carsten Müller-Tidow, Maximilian Felix Blank
Journal: Leukemia (2022)

FLT3 tyrosine kinase inhibitor (TKI) therapy evolved into a standard therapy in FLT3-mutated AML. TKI resistance, however, develops frequently with poor outcomes. We analyzed acquired TKI resistance in AML cell lines by multilayered proteome analyses. Leupaxin (LPXN), a regulator of cell migration and adhesion, was induced during early resistance development, alongside the tyrosine kinase PTK2B which phosphorylated LPXN. Resistant cells differed in cell adhesion and migration, indicating altered niche interactions. PTK2B and LPXN were highly expressed in leukemic stem cells in FLT3-ITD patients. PTK2B/FAK inhibition abrogated resistance-associated phenotypes, such as enhanced cell migration. Altered pathways in resistant cells, assessed by nascent proteomics, were largely reverted upon PTK2B/FAK inhibition. PTK2B/FAK inhibitors PF-431396 and defactinib synergized with different TKIs or daunorubicin in FLT3-mutated AML. Midostaurin-resistant and AML cells co-cultured with mesenchymal stroma cells responded particularly well to PTK2B/FAK inhibitor addition. Xenograft mouse models showed significant longer time to leukemia symptom-related endpoint upon gilteritinib/defactinib combination treatment in comparison to treatment with either drug alone. Our data suggest that the leupaxin-PTK2B axis plays an important role in acquired TKI resistance in AML. PTK2B/FAK inhibitors act synergistically with currently used therapeutics and may overcome emerging TKI resistance in FLT3-mutated AML at an early timepoint.
Genomic Testing in Localized Prostate Cancer Can Identify Subsets of African Americans With Aggressive Disease
Authors: Shivanshu Awasthi, G Daniel Grass, Javier Torres-Roca, Peter A S Johnstone, Julio Pow-Sang, Jasreman Dhillon, Jong Park, Robert J Rounbehler, Elai Davicioni, Alex Hakansson, Yang Liu, Angelina K Fink, Amanda DeRenzis, Jordan H Creed, Michael Poch, Roger Li, Brandon Manley, Daniel Fernandez, Arash Naghavi, Kenneth Gage, Grace Lu-Yao, Evangelia Katsoulakis, Ryan J Burri, Andrew Leone, Cesar E Ercole, Joshua D Palmer, Neha Vapiwala, Curtiland Deville, Timothy R Rebbeck, Adam P Dicker, William Kelly, Kosj Yamoah
Journal: JNCI Journal of the National Cancer Institute (2022)

Abstract Background Personalized genomic classifiers have transformed the management of prostate cancer (PCa) by identifying the most aggressive subsets of PCa. Nevertheless, the performance of genomic classifiers to risk classify African American men is thus far lacking in a prospective setting. Methods This is a prospective study of the Decipher genomic classifier for National Comprehensive Cancer Network low- and intermediate-risk PCa. Study-eligible non–African American men were matched to African American men. Diagnostic biopsy specimens were processed to estimate Decipher scores. Samples accrued in NCT02723734, a prospective study, were interrogated to determine the genomic risk of reclassification (GrR) between conventional clinical risk classifiers and the Decipher score. Results The final analysis included a clinically balanced cohort of 226 patients with complete genomic information (113 African American men and 113 non–African American men). A higher proportion of African American men with National Comprehensive Cancer Network–classified low-risk (18.2%) and favorable intermediate-risk (37.8%) PCa had a higher Decipher score than non–African American men. Self-identified African American men were twice more likely than non–African American men to experience GrR (relative risk [RR] = 2.23, 95% confidence interval [CI] = 1.02 to 4.90; P = .04). In an ancestry-determined race model, we consistently validated a higher risk of reclassification in African American men (RR = 5.26, 95% CI = 1.66 to 16.63; P = .004). Race-stratified analysis of GrR vs non-GrR tumors also revealed molecular differences in these tumor subtypes. Conclusions Integration of genomic classifiers with clinically based risk classification can help identify the subset of African American men with localized PCa who harbor high genomic risk of early metastatic disease. It is vital to identify and appropriately risk stratify the subset of African American men with aggressive disease who may benefit from more targeted interventions.
Gnotobiotic mice housing conditions critically influence the phenotype associated with transfer of faecal microbiota in a context of obesity
Authors: Laurence Daoust, Béatrice S-Y Choi, Anne-Laure Agrinier, Thibault V Varin, Adia Ouellette, Patricia L Mitchell, Nolwenn Samson, Genevieve Pilon, Emile Levy, Yves Desjardins, Mathieu Laplante, Fernando F Anhê, Vanessa P Houde, Andre Marette
Journal: Gut (2022)

Objective Faecal microbiota transplantation (FMT) in germ-free (GF) mice is a common approach to study the causal role of the gut microbiota in metabolic diseases. Lack of consideration of housing conditions post-FMT may contribute to study heterogeneity. We compared the impact of two housing strategies on the metabolic outcomes of GF mice colonised by gut microbiota from mice treated with a known gut modulator (cranberry proanthocyanidins (PAC)) or vehicle. Design High-fat high-sucrose diet-fed GF mice underwent FMT-PAC colonisation in sterile individual positive flow ventilated cages under rigorous housing conditions and then maintained for 8 weeks either in the gnotobiotic-axenic sector or in the specific pathogen free (SPF) sector of the same animal facility. Results Unexpectedly, 8 weeks after colonisation, we observed opposing liver phenotypes dependent on the housing environment of mice. Mice housed in the GF sector receiving the PAC gut microbiota showed a significant decrease in liver weight and hepatic triglyceride accumulation compared with control group. Conversely, exacerbated liver steatosis was observed in the FMT-PAC mice housed in the SPF sector. These phenotypic differences were associated with housing-specific profiles of colonising bacterial in the gut and of faecal metabolites. Conclusion These results suggest that the housing environment in which gnotobiotic mice are maintained post-FMT strongly influences gut microbiota composition and function and can lead to distinctive phenotypes in recipient mice. Better standardisation of FMT experiments is needed to ensure reproducible and translatable results.
Lipid Metabolic Reprogramming Extends beyond Histologic Tumor Demarcations in Operable Human Pancreatic Cancer
Authors: Juho Pirhonen, Ábel Szkalisity, Jaana Hagström, Yonghyo Kim, Ede Migh, Mária Kovács, Maarit Hölttä, Johan Peränen, Hanna Seppänen, Caj Haglund, Jeovanis Gil, Melinda Rezeli, Johan Malm, Peter Horvath, György Markó-Varga, Pauli Puolakkainen, Elina Ikonen
Journal: Cancer Research (2022)

Pancreatic ductal adenocarcinoma (PDAC) is among the deadliest malignancies and potentially curable only with radical surgical resection at early stages. The tumor microenvironment has been shown to be central to the development and progression of PDAC. A better understanding of how early human PDAC metabolically communicates with its environment and differs from healthy pancreas could help improve PDAC diagnosis and treatment. Here we performed deep proteomic analyses from diagnostic specimens of operable, treatment-naïve PDAC patients (n = 14), isolating four tissue compartments by laser-capture microdissection: PDAC lesions, tumor-adjacent but morphologically benign exocrine glands, and connective tissues neighboring each of these compartments. Protein and pathway levels were compared between compartments and with control pancreatic proteomes. Selected targets were studied immunohistochemically in the 14 patients and in additional tumor microarrays, and lipid deposition was assessed by nonlinear label-free imaging (n = 16). Widespread downregulation of pancreatic secretory functions was observed, which was paralleled by high cholesterol biosynthetic activity without prominent lipid storage in the neoplastic cells. Stromal compartments harbored ample blood apolipoproteins, indicating abundant microvasculature at the time of tumor removal. The features best differentiating the tumor-adjacent exocrine tissue from healthy control pancreas were defined by upregulation of proteins related to lipid transport. Importantly, histologically benign exocrine regions harbored the most significant prognostic pathways, with proteins involved in lipid transport and metabolism, such as neutral cholesteryl ester hydrolase 1, associating with shorter survival. In conclusion, this study reveals prognostic molecular changes in the exocrine tissue neighboring pancreatic cancer and identifies enhanced lipid transport and metabolism as its defining features.In clinically operable pancreatic cancer, regions distant from malignant cells already display proteomic changes related to lipid transport and metabolism that affect prognosis and may be pharmacologically targeted.
Risk factors for knee osteoarthritis after traumatic knee injury: a systematic review and meta-analysis of randomised controlled trials and cohort studies for the OPTIKNEE Consensus
Authors: Jackie L Whittaker, Justin M Losciale, Carsten B Juhl, Jonas Bloch Thorlund, Matilde Lundberg, Linda K Truong, Maxi Miciak, Belle Lore van Meer, Adam G Culvenor, Kay M Crossley, Ewa M Roos, Stefan Lohmander, Marienke van Middelkoop
Journal: British Journal of Sports Medicine (2022)

To identify and quantify potential risk factors for osteoarthritis (OA) following traumatic knee injury.
Clustering analysis of geriatric and acute characteristics in a cohort of very old patients on admission to ICU
Authors: Oded Mousai, Lola Tafoureau, Tamar Yovell, Hans Flaatten, Bertrand Guidet, Christian Jung, Dylan de Lange, Susannah Leaver, Wojciech Szczeklik, Jesper Fjolner, Peter Vernon van Heerden, Leo Joskowicz, Michael Beil, Gal Hyams, Sigal Sviri
Journal: Intensive Care Medicine (2022)
Targeting Technology in Underserved Adults With Type 1 Diabetes: Effect of Diabetes Practice Transformations on Improving Equity in CGM Prescribing Behaviors
Authors: Priyanka Mathias, Lakshmi Priyanka Mahali, Shivani Agarwal
Journal: Diabetes Care (2022)

Continuous glucose monitoring (CGM) is associated with improved outcomes in type 1 diabetes, but racial-ethnic disparities exist in use. We were interested in examining whether addressing structural health care barriers would change provider prescribing behaviors to make CGM access more equitable.
When I use a word . . . . Too much healthcare—overconfidence
Authors: Jeffrey K Aronson
Journal: BMJ (2022)

Just as overdetection and overdefinition contribute to a risk of overdiagnosis or misdiagnosis, so does overconfidence. Physicians in general tend to underappreciate the likelihood that their diagnoses are wrong, because of overconfidence in their diagnostic abilities. Overconfidence in one’s intuitive thinking, moulded by long experience, can lead to misdiagnosis if one suppresses one’s analytical thinking; fewer errors are made when both intuitive and analytical thinking are engaged. Furthermore, those who are overconfident tend to adduce evidence that supports their diagnosis and reject evidence that does not. Poorly performing students are more confident in their abilities than their performances suggest, although they also report less confidence in their predictions. Surprisingly, high fidelity (highly realistic) simulation teaching, say with mannequins, may lead to overconfidence and equal or even worse performance and growth in knowledge than low fidelity simulation. Hindsight bias, the tendency to exaggerate the extent to which a past event could have been predicted beforehand, also tends to induce overconfidence.
Human infection with H3N8 avian influenza virus: A novel H9N2-original reassortment virus
Authors: Peidong Li, Minghui Niu, Yitao Li, Mingguo Xu, Tianyi Zhao, Xingwang Cao, Chengzhe Liang, Yong Wang, Yaling Li, Chencheng Xiao
Journal: Journal of Infection (2022)
ACUTE INTERMITTENT PORPHYRIA
Journal: JAMA (1962)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
THE BRITISH MEDICAL ASSOCIATION.
Journal: JAMA (1897)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Immune thrombocytopenia and pregnancy: an exposed/nonexposed cohort study
Authors: Stéphanie Guillet, Valentine Loustau, Emmanuelle Boutin, Anissa Zarour, Thibault Comont, Odile Souchaud-Debouverie, Nathalie Costedoat Chalumeau, Brigitte Pan-Petesch, Delphine Gobert, Stéphane Cheze, Jean Francois Viallard, Anne-Sophie Morin, Gaetan Sauvetre, Manuel Cliquennois, Bruno Royer, Agathe Masseau, Louis Terriou, Claire Fieschi, Olivier Lambotte, Stéphane Girault, Bertrand Lioger, Sylvain Audia, Karim Sacre, Jean Christophe Lega, Vincent Langlois, Alexandra Benachi, Corentin Orvain, Alain Devidas, Sebastien Humbert, Nicolas Gambier, Marc Ruivard, Virginie Zarrouk, Mikael Ebbo, Lise Willems, Lauriane Segaux, Matthieu Mahevas, Bassam Haddad, Marc Michel, Florence Canoui-Poitrine, Bertrand Godeau
Journal: Blood (2022)

The risk of immune thrombocytopenia (ITP) worsening during pregnancy and neonatal ITP (NITP) have never been prospectively studied. We included 180 pregnant and 168 nonpregnant women with ITP in a prospective, multicenter, observational cohort study. A total of 131 pregnant women with ITP were matched to 131 nonpregnant women with ITP by history of splenectomy, ITP status (no response, response, complete response), and duration. Groups were followed for 15 months. The primary outcome was the first occurrence of ITP worsening defined by a composite end point including bleeding events and/or severe thrombocytopenia (<30 × 109/L) and/or ITP treatment modification. We also studied the recurrence of ITP worsening and the incidence of NITP and risk factors. The first occurrence of ITP worsening did not differ between pregnant and nonpregnant women with ITP (53.4 per 100 person-years [95% confidence interval {CI}, 40.8-69.9] vs 37.1 [95% CI, 27.5-50.0]; hazard ratio {HR}, 1.35 [95% CI, 0.89-2.03], P = .16). Pregnant women with ITP were more likely to have recurrence of severe thrombocytopenia and treatment modification (HR, 2.71 [95% CI, 1.41-5.23], P = .003; HR, 2.01 [95% CI, 1.14-3.57], P = .017, respectively). However, recurrence of severe bleeding events was not different between groups (P = .4). Nineteen (14%) neonates showed NITP <50 × 109/L. By multivariable analysis, NITP was associated with a previous offspring with NITP and maternal platelet count <50 × 109/L within 3 months before delivery (adjusted odds ratio, 5.55 [95% CI, 1.72-17.89], P = .004 and 4.07 [95% CI, 1.41-11.73], P = .009). To conclude, women with ITP do not increase their risk of severe bleeding during pregnancy. NITP is associated with NITP history and the severity of maternal ITP during pregnancy. These results will be useful for counseling women with ITP.
Perioperative diagnosis and impact of acquired von Willebrand syndrome in infants with congenital heart disease
Authors: Vanya Icheva, Johanna Ebert, Ulrich Budde, Gesa Wiegand, Sarah Schober, Juliane Engel, Matthias Kumpf, Karl Jaschonek, Felix Neunhoeffer, Jörg Michel, Christian Schlensak, Michael Hofbeck, Harry Magunia
Journal: Blood (2022)
Epo-IGF1R cross talk expands stress-specific progenitors in regenerative erythropoiesis and myeloproliferative neoplasm
Authors: Hsi-Hsien Hsieh, Huiyu Yao, Yue Ma, Yuannyu Zhang, Xue Xiao, Helen Stephens, Naureen Wajahat, Stephen S. Chung, Lin Xu, Jian Xu, Raajit K. Rampal, Lily Jun-shen Huang
Journal: Blood (2022)
A distinct pattern of growth and RAC1 signaling in melanoma brain metastasis cells
Authors: Ioana Stejerean-Todoran, Phyllis A Gimotty, Andrea Watters, Patricia Brafford, Clemens Krepler, Tetiana Godok, Haiyin Li, Zuriñe Bonilla del Rio, Anke Zieseniss, Dörthe M Katschinski, Sinem M Sertel, Silvio O Rizzoli, Bradley Garman, Katherine L Nathanson, Xiaowei Xu, Qing Chen, Jack H Oswald, Michal Lotem, Gordon B Mills, Michael A Davies, Michael P Schön, Ivan Bogeski, Meenhard Herlyn, Adina Vultur
Journal: Neuro-Oncology (2022)

Melanoma, the deadliest of skin cancers, has a high propensity to form brain metastases that are associated with a markedly worsened prognosis. In spite of recent therapeutic advances, melanoma brain lesions remain a clinical challenge, biomarkers predicting brain dissemination are not clear and differences with other metastatic sites are poorly understood.We examined a genetically diverse panel of human-derived melanoma brain metastasis (MBM) and extracranial cell lines using targeted sequencing, a Reverse Phase Protein Array, protein expression analyses, and functional studies in vitro and in vivo.Brain-specific genetic alterations were not detected; however, MBM cells in vitro displayed lower proliferation rates and MBM-specific protein expression patterns associated with proliferation, DNA damage, adhesion, and migration. MBM lines displayed higher levels of RAC1 expression, involving a distinct RAC1-PAK1-JNK1 signaling network. RAC1 knockdown or treatment with small molecule inhibitors contributed to a less aggressive MBM phenotype in vitro, while RAC1 knockdown in vivo led to reduced tumor volumes and delayed tumor appearance. Proliferation, adhesion, and migration were higher in MBM vs nonMBM lines in the presence of insulin or brain-derived factors and were affected by RAC1 levels.Our findings indicate that despite their genetic variability, MBM engage specific molecular processes such as RAC1 signaling to adapt to the brain microenvironment and this can be used for the molecular characterization and treatment of brain metastases.
Corrigendum to “23P - The correlations between knowledge and attitudes of productive age women toward “SADARI” (breast self-assessment) as early detection of breast cancer in Pejeng Kaja Village, Ubud, Bali”
Authors: I.B.Y. Brahmantya, A.B.S. Satyarsa, S.A.A. Suryantari, K.D. Puspitasari, A.T. Adiputra
Journal: Annals of Oncology (2022)
Clinical Trial Development in <i>TP53-</i>Mutated Locally Advanced and Recurrent and/or Metastatic Head and Neck Squamous Cell Carcinoma
Authors: Cristina P Rodriguez, Hyunseok Kang, Jessica L Geiger, Barbara Burtness, Christine H Chung, Curtis R Pickering, Carole Fakhry, Quynh Thu Le, Sue S Yom, Thomas J Galloway, Erica Golemis, Alice Li, Jeffrey Shoop, Stuart Wong, Ranee Mehra, Heath Skinner, Nabil F Saba, Elsa R Flores, Jeffrey N Myers, James M Ford, Rachel Karchin, Robert L Ferris, Charles Kunos, Jean M Lynn, Shakun Malik
Journal: JNCI Journal of the National Cancer Institute (2022)

TP53 mutation is the most frequent genetic event in head and neck squamous cell carcinoma (HNSCC), found in more than 80% of patients with human papillomavirus-negative disease. As mutations in the TP53 gene are associated with worse outcomes in HNSCC, novel therapeutic approaches are needed for patients with TP53-mutated tumors. The National Cancer Institute sponsored a Clinical Trials Planning Meeting to address the issues of identifying and developing clinical trials for patients with TP53 mutations. Subcommittees, or breakout groups, were tasked with developing clinical studies in both the locally advanced and recurrent and/or metastatic (R/M) disease settings as well as considering signal-seeking trial designs. A fourth breakout group was focused on identifying and standardizing biomarker integration into trial design; this information was provided to the other breakout groups prior to the meeting to aid in study development. A total of 4 concepts were prioritized to move forward for further development and implementation. This article summarizes the proceedings of the Clinical Trials Planning Meeting with the goal of developing clinical trials for patients with TP53-mutant HNSCC that can be conducted within the National Clinical Trials Network.